This invention relates to novel potassium channel blocking agents, and their use in the preparation of pharmaceutical compositions.
Moreover the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, in particular asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic hearth disease, angina pectoris, coronary hearth disease, traumatic brain injury, psychosis, anxiety, depression, dementia, memory and attention deficits, Alzheimer""s disease, dysmenorrhea, narcolepsy, Reynaud""s disease, intermittent claudication, Sjorgren""s syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labor, baldness, cancer, and immune suppression.
Ion channels are transmembrane proteins, which catalyze the transport of inorganic ions across cell membranes. The ion channels participate in processes as diverse as the generation and timing of action potentials, synaptic transmissions, secretion of hormones, contraction of muscles, etc.
All mammalian cells express potassium (K+) channels in their cell membranes, and the channels play a dominant role in the regulation of the membrane potential. In nerve and muscle cells they regulate the frequency and form of the action potential, the release of neurotransmitters, and the degree of broncho- and vasodilation.
From a molecular point of view, the K+ channels represent the largest and most diverse group of ion channels. For an overview they can be divided into five large subfamilies: Voltage-activated K+ channels (Kv), long QT related K+ channels (KvLQT), inward rectifiers (KIR), two-pore K+ channels (KTP), and calcium-activated K+ channels (Kca).
The latter group, the Ca2+-activated K+ channels, consists of three well-defined subtypes: SK channels, IK channels and BK channels. SK, IK and BK refer to the single-channel conductance (Small, Intermediate and Big conductance K channel). The SK, IK, and BK channels exhibit differences in e.g. voltage- and calcium-sensitivity, pharmacology, distribution and function.
SK channels are present in many central neurons and ganglia, where their primary function is to hyperpolarize nerve cells following one or several action potentials, in order to prevent long trains of epileptogenic activity to occur. The SK channels are also present in several peripheral cells including skeletal muscle, gland cells, liver cells, and T-lymphocytes. The significance of SK channels in normal skeletal muscle is not clear, but their number is significantly increased in denervated muscle, and the large number of SK channels in the muscle of patients with myotonic muscle dystrophia, suggest a role in the pathogenesis of the disease.
Studies indicate that K+ channels may be a therapeutic target in the treatment of a number of diseases including asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic hearth disease, angina pectoris, coronary hearth disease, traumatic brain injury, psychosis, anxiety, depression, dementia, memory and attention deficits, Alzheimer""s disease, dysmenorrhea, narcolepsy, Reynaud""s disease, intermittent claudication, Sjorgren""s syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labor, baldness, cancer, and immune suppression.
A number of neuromuscular blocking agents with effect on SK channels exist, e.g. apamin, atracurium, pancuronium and tubocurarine.
WO 97/48705 discloses a particular group of chemical compounds useful as calcium activated potassium channel blocking agents. However, their selectivity in respect of the SK channel is not disclosed.
U.S. Pat. No. 5,739,127 and U.S. Pat. No. 5,760,230 disclose other groups of chemical compounds acting on potassium channels.
The present invention resides in the provision of novel chemical compounds capable of selectively blocking SK channels, or subtypes of SK channels.
Moreover the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, including diseases or conditions like respiratory diseases such as asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic hearth disease, angina pectoris, coronary hearth disease, traumatic brain injury, psychosis, anxiety, depression, dementia, memory and attention deficits, Alzheimer""s disease; dysmenorrhea, narcolepsy, Reynaud""s disease, intermittent claudication, Sjorgren""s syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labor, baldness, cancer, and immune suppression.
Accordingly, in its first aspect, the invention provides novel chemical compound of the invention is one selected from the group represented by the general formulas I to VII, below.
In another aspect, the invention provides pharmaceutical compositions comprising an effective amount of a chemical compound of the invention.
In further aspects the invention relates to the use of a chemical compound of the invention for the manufacture of a medicament for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, and to method of treatment or alleviation of disorders or conditions responsive to blockade of potassium channels.
Potassium Channel Blocking Agents
In its first aspect, the invention provides novel chemical compounds. The chemical compounds of the invention is particularly useful as potassium channel blocking agents.
Thus, the invention provides a potassium channel blocking agent, in particular a SK channel blocking agent, selected from the group represented by the general formulas I to VIII, below. 
a bis(aminobenzimidazole) derivative, wherein
A represents a spacing group containing of from 1 to 20 atoms, a spacing group having a chain length of from 1 to 20 atoms, or a spacing group having a chain length comprising of from 1 to 20 separate bonds.
The spacing group, A, may in particular be
a linear or branched alkylene chain having of from 1 to 15 carbon atoms, which alkylene group may be interrupted by one or more oxygen or sulphur atoms, or by one or more groups of the formula xe2x80x94NRxe2x80x2xe2x80x94, or xe2x95x90NRxe2x80x2, wherein Rxe2x80x2 represents hydrogen or alkyl;
a radical of the formula xe2x80x94(CH2)axe2x80x94Dxe2x80x94(CH2)bxe2x80x94, wherein a and b, which may be identical or different, represent the number 0, 1, 2, 3, 4 or 5, and D represents a cycloalkyl group; or
an aryl group of from 6 to 12 carbon atoms, which aryl group may in particular be a phenyl group or a biphenyl group.
In a most preferred embodiment, A is a spacing group selected from those A-groups described in the working examples and in Tables 1, 7 and 8, below, and those B-groups described in the working examples and in Table 8, below.
In a most preferred embodiment, the compound of Formula I is
1,3-Bis[(2-aminobenzimidazol-1-yl)methyl]cyclohexane;
1,6-Bis(2-aminobenzimidazol-1-yl)hexane;
1,4-Bis(2-aminobenzimidazol-1-yl)butane;
1,3-Bis(2-aminobenzimidazol-1-yl)propane;
1,2-Bis(2-aminobenzimidazol-1-yl)ethane;
xcex1,xcex1xe2x80x2-Bis(2-aminobenzimidazol-1-yl)-para-xylene;
xcex1,xcex1xe2x80x2-Bis(2-aminobenzimidazol-1-yl)-meta-xylene;
1,3-Bis(2-aminobenzimidazol-1-yl)benzene;
3,3xe2x80x2-Bis(2-aminobenzimidazol-1-yl)biphenyl; or
cis-1,5-bis(2-amino-1-benzimidazolyl)cyclooctane. 
an aminobenzimidazole derivative, wherein
R1 represents
a mono- or polycyclic aryl group, an aralkyl group, or a mono- or poly-heterocyclic group, which aryl, aralkyl and heterocyclic groups may optionally be substituted one or more times with substituents selected among halogen; alkyl; alkoxy; cyano; trifluoromethyl; phenyl; guanidino, which guanidino may optionally be substituted with alkyl, phenyl or benzyl; primary, secondary or tertiary amino groups, i.e. an amino group substituted once or twice with an alkyl group (xe2x80x94NH2; xe2x80x94NH-alkyl; and xe2x80x94N(alkyl)2); or
a mono- or polycyclic aryl group as described above, attached to a mono- or poly-heterocyclic group described above; and
R2 represents hydrogen, an alkyl group, or CF3.
An example of a preferred aryl group is phenyl.
An example of a preferred aralkyl group is benzyl.
Examples of preferred heterocyclic groups are pyrazolyl, imidazolyl, thiazolyl, and isothiazolyl.
In a more preferred embodiment R1 is a mono- or polycyclic aryl group or a mono- or poly-heterocyclic group selected from those R1-groups described in the working examples and in Table 2, below. In a more preferred embodiment R1 is phenyl, benzyl, pyrazolyl, imidazolyl, thiazolyl, or isothiazolyl.
In a most preferred embodiment R2 represents a substituent selected from those R2-groups described in the working examples and in Table 2, below.
In a most preferred embodiment, the compound of Formula II is
2-Amino-1-[4-(4-chlorophenyl)-2-thiazolyl]benzimidazole;
2-Amino-1-(4-dimethylaminobenzyl)-5-trifluoromethylbenzimidazole;
2-Amino-1-(4-phenyl-2-thiazolyl)benzimidazole;
2-Amino-1-[3-(1,3,5-trimethylpyrazol-4-yl)phenyl]benzimidazole;
2-Amino-1-(4-(N-(2-thiazolyl)amino)phenyl)benzimidazole;
1-(4-(2-Aminobenzimidazol-1-yl)phenyl)-3-phenylguanidine;
2-Amino-1-(4-acetamidophenyl)benzimidazole; or
2-Amino-1-(4-aminophenyl)-benzimidazole. 
a guanidine derivative, wherein
R1 and R2, which may be identical or different, represent hydrogen, alkyl, a mono- or poly-heterocyclic group, a mono- or polycyclic aryl group, or an aralkyl group, which heterocyclic, aryl or aralkyl groups may optionally be substituted one or more times with substituents selected among halogen; alkyl; alkoxy; cyano; trifluoromethyl; phenyl; guanidino, which guanidino may optionally be substituted with alkyl, phenyl or benzyl; or primary, secondary or tertiary amino groups, i.e. an amino group substituted once or twice with an alkyl group (xe2x80x94NH2; xe2x80x94NH-alkyl; and xe2x80x94N(alkyl)2).
Examples of preferred heterocyclic monocyclic groups of the invention are furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, and thienyl.
Examples of preferred heterocyclic polycyclic groups of the invention are benzimidazolyl, indolyl, isoquinolyl, quinolyl, acridinyl, phenazinyl, and phenthiazinyl. Examples of preferred aryl groups of the invention are phenyl, naphthyl and anthracenyl.
A preferred aralkyl group of the invention is benzyl.
In a most preferred embodiment, R1 represents substituent selected from those R1-groups described in the working examples and in Table 3, below.
In a most preferred embodiment, R2 represents a substituent selected from those R2-groups described in the working examples and in Table 3, below.
In a most preferred embodiment the compound of Formula III is
1-(2-Methoxy-5-(trifluoromethyl)phenyl)-3-(3-(trifluoromethyl)phenyl)guanidine;
1-(4-Chlorobenzyl)-3-(3-triflouromethylphenyl)guanidine;
1-(5-Chloro-2-methoxyphenyl)-3-(3-(trifluoromethyl)phenyl)guanidine;
1,3-Bis(3-(trifluoromethyl)phenyl)guanidine;
1-(2-Bromo-5-(trifluoromethyl)phenyl)-3-(5-(trifluoromethyl)phenyl)guanidine;
1-(4-aminophenyl)guanidine;
xcex1,xcex1xe2x80x2-Bis(3-phenylguanidine-1-yl)-para-xylene; or
6-Amino-3-guanidinoacridine. 
a guanidine derivative, wherein
R1 and R2, which may be identical or different, represents hydrogen, a mono- or polycyclic aryl group, or an aralkyl group, which aryl or aralkyl groups may optionally be substituted one or more times with substituents selected among halogen, alkyl, alkoxy, cyano, trifluoromethyl, primary, secondary or tertiary amino groups, i.e. an amino group substituted once or twice with an alkyl group (xe2x80x94NH2; xe2x80x94NH-alkyl; and xe2x80x94N(alkyl)2); and
R3 represents
a divalent mono- or poly-heterocyclic group, a divalent mono- or polycyclic aryl group, or a divalent aralkyl group, which heterocyclic, aryl, aralkyl may optionally be substituted one or more times with substituents selected among halogen, alkyl, alkoxy, cyano, trifluoromethyl, primary, secondary or tertiary amino groups, which secondary and tertiary amino groups may substituted (once or twice) with an alkyl group or a phenyl group, said phenyl group optionally being substituted one or more times with substituents selected among halogen, trifluoromethyl, and/or cyano;
a divalent radical of the formula xe2x80x94(CH2)cxe2x80x94, wherein c is a number 1, 2, 3, 4 or 5; or
a mono- or polycyclic aryl group as described above, attached to another mono- or polycyclic aryl group as described above, optionally attached via an oxygen, sulphur, or nitrogen atom to form a divalent bridging group, in which bridging group the nitrogen atom may additionally be substituted with a mono- or polycyclic aryl group as described above to form a tertiary amino group.
Examples of preferred R1 and R2 groups are phenyl and benzyl, optionally substituted one or more times with halogen and/or a primary amino group. The substitutions may preferably be in the ortho- and/or para-positions.
Examples of preferred R3 groups are divalent phenyl groups, or divalent phenyl groups bridged by a nitrogen atom to form a secondary or tertiary amino group, which tertiary amino group may preferably be substituted with an additional phenyl group, which phenyl group may optionally be substituted with halogen, trifluoromethyl or cyano.
In a most preferred embodiment R1 represents a substituent selected from those R1-groups described in the working examples and in Table 4, below.
In a most preferred embodiment R2 represents a substituent selected from those R2-groups described in the working examples and in Table 4, below.
In a most preferred embodiment R3 represents a substituent selected from those R3-groups described in the working examples and in Table 4, below.
In a most preferred embodiment the compound of Formula IV is
5-Chloro-1,3-bis-(4-chlorobenzyl)-2-iminobenzimidazoline;
12-(3-Chloro-4-cyanophenyl)-6-imino-5,7,12-triaza-di-benzo[a,f]cyclooctane;
1-(2-Aminophenyl)-2-imino-3-phenyl-imidazolidine; or
6-Imino-5,7,12-triaza-di-benzo[a,f]cyclooctane.
Formula V
Rxe2x80x94Lxe2x80x94Rxe2x80x83xe2x80x83(V)
representing symmetric compounds wherein
L represents a spacing group containing of from 1 to 20 atoms, a spacing group having of from 2 to 20 atoms, or a spacing group comprising of from 2 to 20 separate bonds; and
R represents
a mono- or polycyclic aryl group, an aralkyl group, or one or more mono- or poly-heterocyclic group(s), which heterocyclic group preferably comprises one or more nitrogen atoms as the heteroatom(s),
or a mono- or polycyclic aryl group or an aryl group attached to a heterocyclic group as described above.
The R-group holding a tertiary nitrogen atom may in particular be made quaternary using an alkylation agent, preferably an alkyl halide, such as the chloride, bromide or iodide of methyl or ethyl.
The spacing group, L, may in particular be
a linear or a branched alkylene chain having of from 2 to 5 carbon atoms;
a radical of the formula xe2x80x94(CH2)axe2x80x94Dxe2x80x94(CH2)bxe2x80x94, wherein a and b, which may be identical or different, represent the number 0, 1, 2, 3, 4 or 5, and D represents a cycloalkyl group;
an aryl group of from 6 to 12 carbon atoms, which aryl group may in particular be a biphenyl group; or
a mono- or poly-heterocyclic group, which heterocyclic group preferably comprise one or more nitrogen atoms as the heteroatom(s).
An example of a preferred aryl group is phenyl.
Examples of preferred heterocyclic groups are pyrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and piperazinyl.
The R group may preferably be
a nitrogen containing heterocyclic ring attached to a nitrogen containing hetero-aromatic ring (heteroaryl), wherein the nitrogen containing heterocyclic ring preferably is piperazinyl, and the nitrogen containing heteroaryl preferably is pyrimidinyl; or
a nitrogen containing hetero-aromatic ring (heteroaryl), wherein the nitrogen containing heterocyclic ring preferably is benzimidazolyl, attached to an aralkyl group, wherein the aralkyl group preferably is benzyl.
In a most preferred embodiment L represents a spacing group selected from those L-groups described in the working examples and in Table 5, below.
In a most preferred embodiment R represents a substituent selected from those R-groups described in the working examples and in Table 5, below.
In a most preferred embodiment the compound of Formula V is
xcex1,xcex1xe2x80x2-Bis(1-(2-pyrimidyl)piperazin-4-yl)-para-xylene;
xcex1,xcex1xe2x80x2-Bis(1-(2-pyrimidyl)-4-methylpiperazinium-4-yl)-para-xylene; or
1,4-Bis(1-benzylbenzimidazol-2-yl)piperazine. 
wherein
R1, R2, and R4, which may be identical or different, represent hydrogen, alkyl, phenyl or benzyl, which phenyl or benzyl may optionally be substituted one or more times with substituents selected among halogen, trifluoromethyl, and cyano; and
R3 represents hydrogen, halogen, trifluoromethyl, cyano, alkyl, phenyl or benzyl.
In a most preferred embodiment R1 represents a substituent selected from those R1-groups described in the working examples and in Table 6, below.
In a most preferred embodiment R2 represents a substituent selected from those R2-groups described in the working examples and in Table 6, below.
In a most preferred embodiment R3 represents a substituent selected from those R3-groups described in the working examples and in Table 6, below.
In a most preferred embodiment R4 represents a substituent selected from those R4-groups described in the working examples and in Table 6, below.
In a most preferred embodiment the compound of Formula VI is
1-(4xe2x80x2-Chlorobenzyl)-2-dimethylamino)-5-trifluoromethylbenzimidazoline. 
a bis(benzimidazole) derivative, wherein
A is a spacing group with the meanings described for group A under Formula I, above, and
X represents
hydrogen, halogen, trifluoromethyl, cyano, alkoxy, alkyl, phenyl or benzyl, which phenyl or benzyl may optionally be substituted one or more times with substituents selected among halogen, trifluoromethyl, and alkyl; or
a mono- or poly-heterocyclic group, preferably comprising one or more nitrogen, oxygen or sulphur atoms as heteroatom(s), which heterocyclic group may optionally be substituted one or more times with substituents selected among halogen, trifluoromethyl, alkoxy or alkyl.
In a most preferred embodiment A represents a spacing group selected from those A-groups described in the working examples and in Table 7, below.
In a most preferred embodiment X represents a substituent selected from those X-groups described in the working examples and in Table 7, below.
In a most preferred embodiment the compound of Formula VII is
cis,trans-1,4-Bis[(2-chlorobenzimidazol-1-yl)methyl]cyclohexane;
cis,trans-1,4-Bis[2-(1-pyrrolidinyl)benzimidazol-1-yl)methyl]cyclohexane;
cis,trans-1,4-Bis[(2-(4-morfolinyl)benzimidazol-1-yl)methyl]cyclohexane;
cis,trans-1,4-Bis[(2-(1-methylpiperazine-4-yl)benzimidazol-1-yl)methyl]cyclohexane; or
xcex1,xcex1xe2x80x2-Bis(1-benzimidazolyl)-meta-xylene. 
a bis(benzimidazolium) derivative, wherein
A and B, which may be identical or different, represent spacing groups as described for group A under Formula I, above;
X is as described under Formula VII, above; and
Y represents a halide, and is preferably chlorine, bromine or iodine.
In a most preferred embodiment A and B represents a spacing group selected from those A-groups described in the working examples and in Tables 1, 7 and 8, below.
In a most preferred embodiment the compound of Formula VIII is
1,1xe2x80x2-(xcex1,xcex1xe2x80x2-para-xylylene)-3,3xe2x80x2-(xcex1,xcex1xe2x80x2-meta-xylylene)-bis(benzimidazolium).
Definition of Substituents
In the context of this invention a spacing group designates a substituent that links the two parts of the molecule and bring these parts into a relatively determined spatial inter-relationship. The spacing group may also be termed a linking group or a bridging group. The spacing group of the invention should link the two parts of the molecule in a not too close and not too far distance from each another. It is currently believed that spacing groups comprising of from 2 to 20 atoms fulfill this requirement. Examples of such spacing groups are described herein, and summarized below.
In the context of this invention halogen represents a fluorine, a chlorine, a bromine or a iodine atom.
In the context of this invention an alkyl group designates a univalent saturated, straight or branched hydrocarbon chain. The hydrocarbon chain preferably contain of from one to eighteen carbon atoms (C1-18-alkyl), more preferred of from one to six carbon atoms (C1-6-alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl. In a preferred embodiment alkyl represents a C1-4-alkyl group, including butyl, isobutyl, secondary butyl, and tertiary butyl. In a preferred embodiment of this invention alkyl represents a C1-3-alkyl group, which may in particular be methyl, ethyl, propyl or isopropyl.
In the context of this invention a cycloalkyl group designates a cyclic alkyl group, preferably containing of from three to seven carbon atoms (C3-7-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In the context of this invention an alkoxy group designates an xe2x80x9calkyl-Oxe2x80x94xe2x80x9d group, wherein alkyl is as defined above.
In the context of this invention an amino group may be a primary (xe2x80x94NH2), secondary (xe2x80x94NH-alkyl), or tertiary (xe2x80x94N(alkyl)2) amino group, i.e. it may be substituted once or twice with an alkyl group as defined above.
In the context of this invention a mono- or polycyclic aryl group designates a monocyclic or polycyclic aromatic hydrocarbon group. Examples of preferred aryl groups of the invention are phenyl, naphthyl and anthracenyl.
In the context of this invention an aralkyl group designates a mono- or polycyclic aryl group as defined above, which aryl group is attached to an alkyl group as also defined above. An example of a preferred aralkyl group of the invention benzyl.
In the context of this invention a mono- or poly-heterocyclic group is a mono- or polycyclic compound, which holds one or more heteroatoms in its ring structure. One or more of the ring structures may in particular be aromatic (i.e. a heteroaryl). Preferred heterocyclic monocyclic groups of the invention are 5- or 6 membered heterocyclic monocyclic groups. Examples of preferred heterocyclic monocyclic groups of the invention are furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, and thienyl. Examples of preferred heterocyclic polycyclic groups of the invention are benzimidazolyl, indolyl, isoquinolyl and quinolyl.
Also, in the context of this invention, a chemical compound comprising a tertiary amino group may also be made quaternary (quaternized) using an alkylation agent, in particular an alkyl halide, preferably the chloride, bromide or iodide of methyl or ethyl.
Specific Examples
In its most preferred embodiment, the chemical compound of the invention is one selected from those described in the working examples or in Tables 1-8, below.
Steric Isomers
The chemical compounds of the present invention may exist in (+) and (xe2x88x92) forms as well as in racemic forms. The racemates of these isomers and the individual isomers themselves are within the scope of the present invention.
Racemic forms can be resolved into the optical antipodes by known methods and techniques. One way of separating the diastereomeric salts is by use of an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallization of d- or l- (tartrates, mandelates, or camphorsulphonate) salts for example.
The chemical compounds of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (xe2x88x92) phenylalanine, (+) or (xe2x88x92) phenylglycine, (+) or (xe2x88x92) camphanic acid or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like.
Additional methods for the resolving the optical isomers are known in the art. Such methods include those described by Jaques J, Collet A, and Wilen S in xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, New York (1981).
Moreover, some of the chemical compounds of the invention being oximes, may thus exist in two forms, syn- and anti-form (Z- and E-form), depending on the arrangement of the substituents around the xe2x80x94Cxe2x95x90Nxe2x80x94 double bond. A chemical compound of the present invention may thus be the syn- or the anti-form (Z- and E-form), or it may be a mixture hereof.
Pharmaceutically Acceptable Salts
The chemical compound of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms of the chemical compound of the invention.
Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, the formate derived from formic acid, the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulfonate derived from benzensulfonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, the malonate derived from malonic acid, the mandelate derived from mandelic acid, the methanesulfonate derived from methane sulphonic acid, the naphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, the phthalate derived from phthalic acid, the salicylate derived from salicylic acid, the sorbate derived from sorbic acid, the stearate derived from stearic acid, the succinate derived from succinic acid, the tartrate derived from tartaric acid, the toluene-p-sulphonate derived from p-toluene sulphonic acid, and the like. Such salts may be formed by procedures well known and described in the art.
Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
Metal salts of a chemical compound of the invention includes alkali metal salts, such as the sodium salt of a chemical compound of the invention containing a carboxy group.
The chemical compound of the invention may be provided in dissoluble or indissoluble forms together with a pharmaceutically acceptable solvents such as water, ethanol, and the like. Dissoluble forms may also include hydrated forms such as the monohydrate, the dehydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, the dissoluble forms are considered equivalent to indissoluble forms for the purposes of this invention.
Methods of Preparation
The chemical compounds of the invention may be prepared by conventional methods of chemical synthesis, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.
The end products of the reactions described herein may be isolated by conventional techniques, e.g. by extraction, crystallization, distillation, chromatography, etc.
Biological Activity
The chemical compounds of the invention have been subjected to in vitro experiments and found particularly useful as potassium channel blocking agents. More particularly the compound of the invention are capable of selectively blockade of SK channels, e.g. SK1, SK2 and/or SK3 channels.
As described in the working examples, the compounds tested all showed a biological activity determined as IC50 in the sub-micromolar and low micromolar range, i.e. of from below 1 to above 10 xcexcM. Preferred compounds of the invention show a biological activity determined as described herein in the in the sub-micromolar and micromolar range, i.e. of from below 1 to about 100 xcexcM.
Therefore, in another aspect, the invention relates to the use of a chemical compound of the invention for the manufacture of medicaments, which medicament may be useful for the treatment or alleviation of a disease or a disorder associated with the activity of potassium channels, in particular SK channels.
In a more preferred embodiment, the chemical compound of the invention may be use for the manufacture of medicaments for the treatment or alleviation of diseases or conditions like respiratory diseases such as asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic hearth disease, angina pectoris, coronary hearth disease, traumatic brain injury, psychosis, anxiety, depression, dementia, memory and attention deficits, Alzheimer""s disease, dysmenorrhea, narcolepsy, Reynaud""s disease, intermittent claudication, Sjorgren""s syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labor, baldness, cancer, and immune suppression.
Pharmaceutical Compositions
In yet another aspect the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention.
While a chemical compound of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers and/or diluents.
In a preferred embodiment, the invention provides pharmaceutical compositions comprising the chemical compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical compositions of the invention may be those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration, or those in a form suitable for administration by inhalation or insufflation.
The chemical compound of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
The chemical compound of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention.
For preparing pharmaceutical compositions from a chemical compound of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glyceride or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
The chemical compound according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
For topical administration to the epidermis the chemical compound according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
Compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.
Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
When desired, compositions adapted to give sustained release of the active ingredient may be employed.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
Further details on techniques for formulation and administration may be found in the latest edition of Remington""s Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
A therapeutically effective dose refers to that amount of active ingredient which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity, e.g. ED50 and LD50, may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by the ratio LD50/ED50. Pharmaceutical compositions which exhibit large therapeutic indexes are preferred.
The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.
The active ingredient may be administered in one or several doses per day. It is presently contemplated that compositions containing of from about 0.1 to about 500 mg of active ingredient per unit dosage, preferably of from about 1 to about 100 mg, most preferred of from about 1 to about 10 mg, are suitable for therapeutic treatments.
Methods of Treatment
In another aspect the invention relates to a method of treating or alleviating a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to blockade of the potassium channel, in particular the SK channel, which method comprises comprising administering to such a living animal body, including a human, in need thereof a therapeutically-effective amount of a compound of the invention.
The in a preferred embodiment of the method of the invention, the disease or disorder is asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic hearth disease, angina pectoris, coronary hearth disease, traumatic brain injury, psychosis, anxiety, depression, dementia, memory and attention deficits, Alzheimer""s disease, dysmenorrhea, narcolepsy, Reynaud""s disease, intermittent claudication, Sjorgren""s syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labor, baldness, cancer, and immune suppression.
A satisfactory result can, in certain instances, be obtained at a dosage as low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o. The upper limit of the dosage range is about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from about 0.001 to about 1 mg/kg i.v. and from about 0.1 to about 10 mg/kg p.o.